Self-injurious behavior (SIB) is a major clinical problem among mentally retarded children and adults. Despite considerable research effort, the determinants of SIB remain largely unknown, and currently used therapeutic measures have had limited success. The lack of progress toward understanding and treating SIB can be attributed, in part, to a paucity of research concerning the neurobiological basis of this behavior. Studies with both animals and humans suggest that this behavior is related to aberrant neurochemical processes in the substantia nigra and its output stations. The major objective of the studies outlined in this proposal is to examine the role played by each of these structures in SIB produced by microinjecting the GABA agonist muscimol into the substantia nigra of rats. This will be accomplished by examining the effect of lesioning discrete brain regions on muscimol-induced SIB. It is hypothesized that the brain areas under investigation play a role in the production of SIB by mediating one of two processes: 1) a tendency toward perseverative motor acts, and 2) alterations in nocieceptive thresholds. Each of these processes will be investigated in brain regions found to regulate muscimol-induced SIB. A final objective of this proposal is the development of an animal model of SIB that involves alterations in dopamine systems in the basal ganglia. Recent evidence suggests that perturbations in striatal dopamine function are related to the SIB seen in Lesch-Nyhan patients. Studies are planned to determine whether SIB produced by enhancing dopamine transmission in the striatum is mediated by the substantia nigra.